For messenger RNA (mRNA) therapeutics and vaccines formulated as lipid nanoparticles (LNPs), the excipients receiving the most attention are the encapsulating lipids. While these compounds are crucial to the stability and delivery of mRNA-LNPs, the non-lipid excipients also play crucial roles in the function of final drug products. They impact the morphology and stability of these delivery systems, which in turn affects in vivo performance and the overall usefulness of mRNA drugs developed using nanoparticle technology.

The Real Message Behind Commercial mRNA Products

Cynthia A. Challener, PhD has been a freelance technical writer for over 20 years and contributes regularly to 


eBook: The Real Message Behind Commercial mRNA Products
April 2023
Pages: 22–25

When referring to this article, please cite it as Challener, C. A. Excipients Impact Stability in mRNA-LNP Formulations. 

Pharmaceutical Technology's The Real Message Behind Commercial mRNA Products

 This article was originally published in 

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Lipids aren’t the only important ingredients influencing stability and in vivo performance.

Stability in mRNA-LNP Formulations

Nucleic acid-based therapeutics have been stepping up into the spotlight following the deployment of messenger RNA (mRNA) COVID-19 vaccines in 2021 and the rise in clinical development programs for gene therapies. These areas of development may just be the surface of the types of therapeutic applications where nucleic acid-based therapeutics can come into play. Tackling the development challenges of these therapeutics can potentially benefit more expansive areas of unmet medical need, particularly in difficult-to-treat patient populations.


eBook: The Real Message Behind Commercial mRNA Products
April 2023
Pages: 12–17

When referring to this article, please cite it as Mirasol, F. Nucleic Acid-based Therapeutics Are Stepping into the Spotlight. 

Pharmaceutical Technology's The Real Message Behind Commercial mRNA Products 

The recent success of mRNA vaccines has opened the door for further and future development of nucleic acid-based therapies.

Nucleic Acid-based Therapeutics Are Stepping into the Spotlight

World leaders have set ambitious goals to respond more swiftly to the next pandemic, including the United States’ goal to design, test, and review a new vaccine just 100 days after a pandemic declaration and to produce enough vaccines for the US and the world in 130 and 200 days. Past preparedness efforts have focused on innovation and reliability—culminating in the novel mRNA vaccines. Today, it’s important to consider diverse responses—and how the industry can make investments sustainable and “ready” for when an emergency happens.


eBook: The Real Message Behind Commercial mRNA Products
April 2023
Pages: 6–11

When referring to this article, please cite it as Spivey, C. Learning to Think at Lightspeed. 

Actions combatting the next pandemic must be diverse, reliable, and sustainable.

Learning to Think at Lightspeed

Oligonucleotide drug substances generally are unstable at room temperature, and some are also degraded in the presence of certain enzymes. That is why, in part, they are formulated using special delivery solutions such as lipid nanoparticles (LNPs). (These delivery technologies also facilitate entry of nucleotide APIs into target cells.) Degradation can occur via loss of terminal nucleotides or certain functional groups, oxidation, and other mechanisms. Oligonucleotide–oligonucleotide interactions that can occur at higher concentrations are an added concern. These instability issues must be managed throughout the entire manufacturing process.

The challenges are particularly great for messenger RNA (mRNA), which can be degraded by enzymes found commonly in the environment, temperature, and due to the overall shear sensitivity of the
long-chained molecule.

 This article was previously published in 

Cynthia A. Challener, PhD, is a contributing editor to 

When referring to this article, please cite it as Challener, C. A. Managing mRNA Instability During Formulation, Manufacturing, and Shipment. 

Unique solutions are required to protect inherently unstable messenger RNA.

Managing mRNA Instability

Messenger ribonucleic acids (mRNA) therapeutics are becoming more widespread pharmaceutical tools to treat a wide range of diseases or infections, as highlighted by regulatory approval of two vaccines for SARS‑CoV-2. Alongside their use as vaccines, they also play a role in protein replacement therapy to ensure therapeutic protein is synthesized within the patient. Structural elements, such as the 5’ cap, UTR regions, reading frame, and poly A tail are considered as critical quality attributes (CQAs) that are subject to a range of analytical techniques. However, chromatography and other separation methods are commonly used for characterization and quantification of the drug substance and drug product.

Christina Vanhinsbergh is New Modalities Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.

This article was previously published in 


eBook: The Real Message Behind Commercial mRNA Products
April 2023
Pages: 40–49

When referring to this article, please cite it as Vanhinsbergh, C. The Role of Separation Techniques in the Analysis of mRNA Therapeutic Drug Substances and Drug Products. 

This article reviews a range of techniques available for separative analysis of mRNA therapeutics, their associated impurities, and delivery vehicles.

The Role of Separation Techniques in the Analysis of mRNA Therapeutic Drug Substances and Drug Products

For several years after Crick (1) first described the genetic role of RNA, this molecular entity was perceived simply as an “inert” carrier between DNA and protein. Today, however, this view has almost entirely changed, and RNA-based molecules have been implicated in a broad range of functions including the activation/deactivation of genes, the excision of genetic material, and the transport of intercellular components. Indeed, it is expected that in the coming years, further discoveries will uncover even greater biochemical significance to this molecular type.

Given the ubiquity and variety of roles associated with RNA, it was inevitable that it would become a focus for investigators involved in the development of therapeutics. As early as 1978, Zamecnik (2) described the therapeutic use of an RNA-based oligonucleotide to inhibit replication of the Rous sarcoma virus, and, today, there are approximately 16 FDA-approved RNA therapies, 28 in clinical development, and many more expected in the near future (3).

Currently, RNA-based medicines can be segregated by their functionality and structure and include species, such as messenger RNA (mRNA), antisense oligonucleotides (ASO), small interfering RNA (siRNA), and microRNA (miRNA). Other types of RNA include aptamers which are single-stranded and form higher-order structures, and more recently described, circular RNA (circRNA or oRNA), which appears to have multiple functions prior to and following the transcription process (4). Additionally, mature clustered, regularly interspaced, short palindromic repeats RNA (crRNA) and trans-activating CRISPR RNA (tracrRNA) constitute components of the recently developed CRISPR technology.

 The Real Message Behind Commercial mRNA Products

Mark Rogers is global scientific director at SGS.

When referring to this article, please cite it as Rogers, M. The Marriage of RNA and Mass Spectrometry. 

Considerable efforts have been made over the years to resolve the key issues of stability and delivery of RNA-based therapeutics.

The Marriage of RNA and Mass Spectrometry

RNA has been likened to software; once a delivery method is discovered, the sequence can be changed to produce any protein in the body. However, the apparent simplicity of the principle belies the complexity of the production process, and many challenges remain.

Messenger RNA (mRNA) prophylactic vaccines achieved major breakthroughs during the COVID-19 pandemic, gaining approval in more than 150 countries. The speed with which these vaccines were taken to market was a testament to the drive of the innovators, suppliers, and regulatory bodies involved. Now that the general principle is proven, there is much work to do to fully exploit the potential of mRNA in non-COVID infectious diseases, such as immuno-oncology, auto-immune diseases, protein replacement therapies, and gene-editing, to name but a few applications.

David Ricketts is director of Business Development; Nevin Witman is a consultant for etherna; Phil Challis is VP Product Development; Senne Dillen is senior scientist Drug Substance and Drug Product Development; and Bernard Sagaert is interim CEO, all with etherna.

When referring to this article, please cite it as Ricketts, D.; Witman, N.; Challis, P.; Dillen, S.; Sagaert, B. Delivering on the Potential of mRNA Therapeutics. 

The complexity of the RNA production process creates challenges.

Delivering on the Potential of mRNA Therapeutics

RNA-based therapeutics have been in development for decades. The RNA drug development trend was on the rise in early 2000s; however, its popularity went down due to unique challenges. The COVID-19 pandemic helped to bring a spotlight on RNA molecules and their therapeutic potential.There were also lessons learned in terms of drug delivery, manufacturing, logistics and storage. This is the silver lining of the pandemic, where necessity and emergency need for vaccine and therapy highlighted potential solutions. Hopefully, it also opens the door for novel RNA therapeutics.

Marina Necdina is a business development manager, former pharma analyst, and research scientist.

When referring to this article, please cite it as Necdina, M. The COVID-19 Pandemic and Its Positive Impact on RNA Drug Development. 

 This article was original published online on Feb. 1, 2023 and updated on April 11, 2023 to include missing text.

The COVID-19 pandemic helped to showcase RNA molecules and their therapeutic potential.  There were also lessons learned in terms of drug delivery, manufacturing, logistics, and storage. 

The Real Message Behind Commercial mRNA Products, April 2023 eBook